Pharmaceutical formulation comprising more than 15% tamoxifen

ABSTRACT

The invention provides a pharmaceutical formulation comprising &gt;15% tamoxifen (w/w). In a further embodiments of the invention the invention provides said formulation further comprising from about 0.45% to 1% (w/w) anastrozole. The invention also provides said formulation in the form of a tablet and processes for the preparation of said formulation.

This application is a national stage filing under 35 U.S.C. 371 ofInternational Application No. PCT/GB02/04835, filed Oct. 23, 2002, whichclaims priority from United Kingdom Patent Application No. 0125492.9,filed Oct. 24, 2001, the specification of which is incorporated byreference herein. International Application No. PCT/GB02/04835 waspublished under PCT Article 21(2) in English

Tamoxifen is an anti-estrogen used in the treatment and prevention ofbreast cancer. A challenge facing workers for making a solid doseformulation of tamoxifen is in providing a formulation having a highpercentage of tamoxifen citrate (e.g., >15% w/w). Further challenges arein providing a low dose of an aromatase inhibitor such as anastrozole incombination with a high percentage of tamoxifen. Provided herein is apharmaceutical formulation comprising >15% tamoxifen by weight (w/w),preferably up to 23%. Thus, according to the invention there is provideda pharmaceutical formulation comprising >15% of tamoxifen furthercomprising:

-   a) an effective amount of a diluent;-   b) an effective amount of a disintegrant;-   c) an effective amount of a binder; and-   d) an effective amount of a lubricant;    wherein said formulation comprises granules having a moisture    content of less then or equal to 2% w/w and having a granule surface    area of from about 30,000 to about 55,000 cm²/100 g. In reference    the percentages “(w/w)” refers to the mass of a component in ratio    to the mass of the total amount of the formulation unless otherwise    noted. Tamoxifen citrate is preferred but the formulation described    herein also applies to other salts of tamoxifen and to the    equivalent amount of free base. tamoxifen may be provided up to    about, by weight, 23% (w/w). Preferably, Tamoxifen may be provided    in the range 16% to 20% (w/w), most preferably between 16.5% and    17.5% (w/w). Tamoxifen may be provided in the formulation in    combination with an aromatase inhibitor. Aromatase inhibitors that    may be used in the current invention are, for example, anastrozole,    formestane, atamestane, letrozole, pentrozole, dadrozloze, or    vorozole. In a surprising aspect of the invention, a formulation    provides, at a low concentration of the aromatase inhibitor, good    content uniformity for the aromatase inhibitor. Anastrozole may be    provided herein in a low concentration, for example, in an amount    from about 0.45% to about 1% (w/w), preferably 0.45% up to about    0.80% (w/w), yet more preferably from about 0.5% up to about 0.67%    (w/w), more preferably from 0.50% up to about 0.70% (w/w) and most    preferably at 0.56% (w/w). Anastrozole is a potent and selective    non-steroidal aromatase inhibitor. It is used for example in the    treatment of advanced breast cancer in postmenopausal women with    disease progression following tamoxifen therapy.

The pharmaceutical formulation may be provided with the activeingredients in combination with other active agents. Other ingredientsmay also be provided in the pharmaceutical formulation. Theseingredients may be provided having specifications set out for example inthe 2001 European Pharmacopeia (“PhEur”). The formulation may comprisean effective amount of a binder, for example in an amount, by weight,from 1 to 4% (w/w). Suitable binders for use in the present inventioninclude polymeric binders such as povidone and cellulose binders such ashydroxypropyl methylcellulose. A preferred binder is povidone. Theformulation may further comprise an effective amount of a disintegrant,for example in the amount, by weight, of about 2% to about 5% (w/w).Disintegrants suitable for use herein include, for example, sodiumstarch glycollate and crospovidone. A preferred disintegrant iscroscarmellose sodium. The formulation may further comprise an effectiveamount of at least one diluent, for example in the amount, by weight, ofabout 60% to about 80% (w/w). If two diluents are provided the firstdiluent may be provided in the amount, by weight, of from about 50%(w/w). Suitable diluents that may be used include lactose monohydrateand microcrystalline cellulose. A preferred first diluent is lactosemonohydrate. Lactose monohydrate is preferably provided in combinationwith microcrystalline cellulose in an amount, by weight, of about 55% toabout 75%, preferably about 65% and about 5% to about 20%, preferably10% (w/w) respectively. Combinations of dicalcium phosphate dihydrateand microcrystalline cellulose or mannitol with microcrystallinecellulose also may be used. The formulation may also comprise aneffective amount of a lubricant, for example in the amount, by weight,from about 0.5 to 2% (w/w). Lubricants that may be used herein includefatty acids and their salts. Suitable lubricants that may be usedinclude magnesium stearate and stearic acid, preferably magnesiumstearate.

Further examples of tablet excipients are given in the Handbook ofPharmaceutical Excipients (3^(rd) Edition, 2000), Editor: Kibbe,Publisher: American Pharmaceutical Association, which is incorporatedherein by reference.

These ingredients are used to make granules which may be compressed toform tablet cores or used in other formulations such as in a capsule.The granules are preferably compressed to form a tablet core. The coremay be coated for example by typical coating processes. The coating maycomprise an effective amount of a film former, for examplehydroxypropylmethylcellulose; an effective amount of a plasticiser, forexample a low molecular polyethylene glycol such as polyethylene glycol300; and an effective amount of an opacifier, for example titaniumdioxide.

The ingredient may be provided in an amount effective to provide acontent uniformity of the active agents of 6% RSD (relative standarddeviation). For example, anastrozole in the amount of 0.90 mg to 1.1 mgand tamoxifen free base equivalent in the amount of 18 mg to 22 mg bothhad measured RSD of ≦6% or better in tablets made according to theformulations and methods described herein. The ideal content uniformityfor each drug substance is preferably <2% RSD and can be achieved usingthe formulation and methods described herein.

Further provided herein is a method of making a pharmaceuticalformulation of tamoxifen comprising: 1) mixing tamoxifen, anastrozole,lactose monohydrate, microcrystalline cellulose, croscarmellose sodiumand povidone, to form a dry mixture; 2) mixing the dry mixture withwater to form a wet mass wherein the water may be added to the drymixture for instance by spraying the water onto the dry mix; 3) breakingup large aggregates, for example by passing through a screen; 4) dryingthe granules to a moisture content of less than or equal to 2% (w/w) toform dry granules; 5) milling the dry granules to form milled drygranules; 6) adding a lubricant to the milled dry granules; 7) blendingthe milled dry granules containing the lubricant; and 8) compressing theblend into tablets.

Also provided herein is a method for making a tamoxifen formulationcomprising: 1) charging ingredients, comprising tamoxifen, anastrozole,at least one diluent, a disintegrant, and a binder to a mixer; 2) mixingthe ingredients to form a mixture of ingredients having uniformdistribution; 3) adding water to the mixture of ingredients to form awet mass; 4) passing the wet mass through a screen; 5) drying thegranules to form dried granules having a moisture content of less thanor equal to 2% (w/w); 6) adding a lubricant to the dried granules toform a lubricant:dried granule mixture; 7) milling the lubricant:driedgranule mixture; and 8) blending the milled mixture to form blendedgranules. In an alternative embodiment of this process, the lubricantcan be added after milling such that the granules and lubricant aremilled separately as and then the lubricant added to the granules inreplacement of steps 6) and 7) above.

The granules may be used for example in capsules and tablets. Fortablets the method comprises further compressing the blended granules toform tablet cores. The methods described above may further compriseapplying a film coat wherein said film coat is made by mixing a filmformer, a plasticiser, an opacifier, and water.

The formulations and methods provided herein are useful for treatingpatients with breast cancer, preferably early stage breast cancer, byadministering a formulation described herein to a patient.

A dry mix may be prepared by adding some of the ingredients describedabove, i.e tamoxifen, anastrozole, lactose monohydrate, microcrystallinecellulose, croscarmellose sodium and providone. Preferably, theingredients are provided in layers such as by symmetrical addition, Theingredients are preferably added in a specific order for example, a drymix may be charged to a vessel as follows: {fraction (3/10)} firstdiluent, all of the binder and the second diluent, {fraction (2/10)} ofthe first diluent, ½ of the tamoxifen citrate, all of the anastrozole, ½of the tamoxifen, {fraction (2/10)} of the first diluent, all of thecroscarmellose sodium, and the remainder of the first diluent.

Formulations containing 4% w/w croscarmellose sodium were made by addingthe disintegrant intra-granularly and extra-granularly. Formulationswere made containing disintegrant which was added intragranularly andformulations were made containing half of the disintegrantintragranularly and half extragranularly. The extragranular material wasadded during the lubricant blending stage. Crushing strength anddisintegration time was measured for a composite sample of tablets fromeach batch which were taken during compression. Negligible differencesin tablet crushing strength, disintegration time and granule flow wasobserved for formulations made using intra and extragranulardisintegrant. Hence, it was shown that the addition of a disintegrant ina single step can be used without any detrimental effects to the tabletand granules physical properties.

The dry mix described above should be mixed for a time sufficient toachieve a content uniformity of anastrozole having a measured relativestandard deviation (RSD)≦6% or better. The equipment that may be usedfor the dry mixing step is preferably a high shear mixer granulator.High impeller speeds may improve the content uniformity and homogeneityfor both ingredients.

For example, good content uniformity (RSD<2%) is found over a range ofbatch sizes (e.g., at the 5.4 kg and 18 kg mix size) with a mixing timeof 8 and 10 minutes respectively and where ingredients were charged tothe mixer in layers. Charging the ingredients to the mixer as describedabove results in a material that has good content uniformity for bothtamoxifen and anastrozole.

In carrying out the method of the invention it is preferable to add thebinder (e.g., povidone) during the dry mix stage.

In carrying out the wet granulation step of the methods describedherein, water is typically added to the dry mix in an amount between 53mg/tablet (299 g/kg of dry mix constituents) to about 80 mg/tablet (449g/ kg of dry mix constituents) preferably at about 67 mg/tablet. At 53mg/tablet a finer material is obtained (54% to 71% of the granules <125μm) while still having good flow characteristics with some filming ofthe tablet punches. Water provided at levels of 80 mg/tablet producedcoarse granules having excellent flow but the tablets formed from thesegranules had reduced hardness and prolonged disintegration times.

Extending the wet mixing time by greater than 50% for a batchmanufactured using the optimal level of water, reduces thecompressibility of granules. A total wet mixing time of 7.5 minutes ispreferably used for 18 kg batches. Wet mixing is preferably done at slowimpeller speeds.

Wet granules may be passed though a screen containing square apertures,preferably about 0.375 inches or greater, preferably up to about 0.5inches. In selecting an appropriate aperture size the goal is to producematerial which can be easily fluidized in the fluid bed drier (asassessed visually) to avoid wet mass accumulation and inefficientdrying. The wet granules are dried, preferably after breaking up largeaggregates, to a moisture content of ≦2% w/w. Granules dried to thelevels described above give a preferred compressibility, e.g., acrushing strength of about 6-12, preferably 7-11 Kp (kiliponds), most atabout 9 Kp.

The dried granules may be milled, preferably using a screen having anaperture 0.062 inches or larger.

A lubricant may be added to the milled dry granules. The lubricant, suchas magnesium stearate, may be milled by passing it through a screen. Theaperture of the screen is preferably about 0.041 inches. The generalpurpose of the milling is to de-lump the magnesium stearate. The milleddry granules may be mixed.

The granules, preferably containing the lubricant, are blended and thegranules may be compressed into tablets preferably with a hardnessdescribed above (6 kp or 12 kp preferably with a disintegration time inwater of ≦10 minutes (specific protocols can be found in the USPharmacopoeia and the European Pharmacopoeia). Granules having a surfacearea within the range of about 35,000 to about 50,000 cm²/100 g andexhibit good compressibility. In carrying out certain methods of theinvention it is preferable to apply pre-compression which increases thecrushing strength of the tablets and helps to prevent capping.

The preferred surface area, when used in the formulation, for tamoxifencitrate is greater then 0.95 m²/g and is from 0.5 to 1.5 m²/g foranastrozole.

The tablet described above may be coated. Suitable coatings can beprepared from concentrates, such as Opaspray White M-I-28813 and WhiteSpeedpaste 30001 (D.F. Ansteads Ltd.). For example White Speedpaste30001 comprises 33.3% (w/w) titanium dioxide, 2% (w/w)hydroxypropylmethylcellulose (HPMC 606) and 10% (w/w) industrialmethylated spirit (IMS) as a preservative. Additional ingredients addedduring preparation of coating mixtures from concentrates include: asuitable plastisizer such as polyethylene glycol 300 and a film former,such as hydroxypropylmethylcellulose. This white film coat may be addedto the tablets using for example perforated drum coaters.

The film coat may be applied using conventional perforated drum coaters.For example at scales of approximately 10 kg and 50 kganastrozole/tamoxifen citrate combination tablets have been shown todemonstrate good stability at 6 months at 25° C./60% Relative humidity(RH), 6 months at 40° C./75% RH and 6 months at 50° C. (ambienthumidity). For anastrozole, no more than 0.2% degradation was observedand for tamoxifen citrate, no more than 0.7% degradation was observed.

The invention will now be exemplified with reference to the followingnon-limiting example.

EXAMPLE 1

Tablets were made comprising a combination of anastrozole and tamoxifencitrate with the ingredients as set out in Table 1 which follows. TABLE1 Composition of anastrozole/tamoxifen Citrate white film coatedtablets. Compendial Quantity Ingredient (tablet core) designations(mg/tablet) Tamoxifen Citrate PhEur, USP, JP 30.4 Anastrozole — 1.0Lactose Monohydrate (450 mesh) PhEur, USNF, JP 118.0 MicrocrystallineCellulose (Avicel PhEur, USNF, JP 18.0 PH101) Croscarmellose SodiumPhEur, USNF, JP 7.2 Povidone (K29-32) PhEur, USP, JP 3.6 MagnesiumStearate PhEur, USNF, JP 1.8 Purified Water^(a) PhEur, USP, JP 67.0Nominal tablet core weight 180.0 Quantity Ingredient (film coat)(mg/tablet) Hydroxypropyl Methylcellulose 2910 PhEur, USP, JP 2.70 (6cps) Polyethylene Glycol 300 PhEur, USNF, JP 0.54 Opaspray White(M-1-28813)^(b) 2.70 Purified Water^(a) PhEur, USP 30.0 Nominal coatedtablet weight 184.19^(a)Purified water was used as the granulating fluid during themanufacture of the tablet core and is removed during granule drying.Purified water is also used as# the solvent/carrier fluid during film-coating and is removed duringthe coating process. The quantities of purified water may be modified toaccommodate processing requirements.^(b)Opaspray white (M-1-28813) is a proprietary product supplied byColorcon Ltd., Dartford, Kent, UK which provides titanium dioxide (0.9mg/tablet) and HPMC (0.05 mg/tablet).

A 54 kilogram batch was prepared by preparing three 18 kg mixes andcombining them at the blending stage. The batches were made as follows:A dry mix of the ingredients from Table I, were charged to a bowl of amixer granulator in the following order: ¼ Pharmatose® lactosemonohydrate (DMV International, Veghel, The Netherlands), Plasdone®povidone (International Speciality Products, New Jersey, USA), Avicel®PH-101 microcrystalline cellulose (FMC International, Philadelphia, Pa.,USA), ¼ lactose, ½ tamoxifen citrate, anastrozole, ½ tamoxifen citrate,¼ lactose, Ac-Di.Sol® croscarmellose sodium (FMC International,Philadelphia, Pa., USA) and ¼ lactose. The levels specified wereapproximate and were adjusted to simplify the weighing and chargingprocedure. The powdered ingredients were mixed for 10 minutes in a fixedbowl mixer-granulator. A fast impeller speed was used (e.g., 350 rpm)with no chopper. Purifed water was transferred (66.5 mg/tablet, 373 g/kgof dry mix constituents) to the pressure tank. The water was sprayed onto the dry mix over a duration of approximately 5.5 minutes using theimpeller at slow speed (e.g., about 200 rpm). After 2 minutes of mixing,the chopper was turned on at slow speed (e.g., 1500 rpm). After all thewater was added and the mix inspected, any material adhering to thesides of the bowl or the mixing blades was dislodged. The dry-mix wasfurther mixed to produce a wet mass of a medium consistency, addingwater when necessary. The total wet mixing time was about 8 minutes: Thedry mix contained drug substance at levels of 16.9% w/w for tamoxifencitrate and 0.56% w/w for anastrozole. Good content uniformity wasobtained as determined by HPLC.

The wet granules were passed through a rotary impeller screening millsuch as a Comil (Ytron Quadro, Chesham, Bucks, UK) using a 0.375″ squareaperture screen. The wet granules were transferred to a fluid bed drierand dried to a moisture content of ≦2% w/w as determined by the loss ondrying method.

Magnesium stearate (Mallinckrodt, St Louis, Mo., USA) was added to thedried granules which were passed through a 0.039 inch screen attached toa Comil.

All three 18 kg mixes were combined and blended for 3 minutes in aV-blender. The tablets were compressed using an 8 mm, round, standardconcave plain, chromium tipped tooling using a rotary tablet press, suchas a Manesty Betapress (Manesty Ltd., Liverpool, UK).

The tablets were coated with a white film coat, prepared using OpasprayWhite M-I-28813 and the ingredients are set forth in Table I. The aboveformulation produced good quality tablets with crushing strengths of7-10 kp and disintegration times of 5-9 minutes. The tablets had afriability of less than 0.2%. The content of anastrozole and tamoxifenwas 0.99 mg/tab (1.74% RSD) and 20.61 mg/tab (1.97% RSD) respectively.Dissolution testing showed that at least 85% of each active agent wasreleased within 30 minutes using a USP2 (US Pharmacopoeia) dissolutionapparatus using a paddle speed of 75 rpm and in 1000 ml 0.02 molar HCl,(pH 1.8).

1. A pharmaceutical formulation comprising >15% of tamoxifen and a) aneffective amount of a diluent; b) an effective amount of a disintegrantc) an effective amount of a binder; and d) an effective amount of alubricant; wherein said formulation comprises granules having a moisturecontent of less than or equal to 2% (w/w) and having a granule surfacearea of from about 30,000 to about 55,000 cm ²/100 g tamoxifen.
 2. Apharmaceutical formulation as defined in claim 1, further comprising aneffective amount of anastrozole.
 3. A pharmaceutical formulation asdefined in claim 1 or 2 wherein the formulation is a tablet.
 4. Apharmaceutical formulation as defined in claim 3, further comprising acoating comprising: an effective amount of a film former; an effectiveamount of a plasticiser; and an effective amount of an opacifier.
 5. Apharmaceutical formulation as defined in claim 3 further comprising acoating comprising: a) about 2.75 mg hydroxypropylmethylcellulose; b)about 0.54 mg Polyethylene glycol 300; and c) about 0.90 mg titaniumdioxide.
 6. A pharmaceutical tablet comprising: from about >15% to about20% (w/w) tamoxifen citrate; from about 0.5% to about 0.67% (w/w)anastrozole; from about 1% to about 4% (w/w) of a binder; about 2 to 5%(w/w) disintegrant; and about 0.5 to 2% lubricant.
 7. The tablet asdefined in claim 6, wherein the tablet further comprises a first diluentin an amount from about 60% to about 80% (w/w).
 8. The tablet as definedin claim 7, where the tablet further comprises a second diluent in anamount from about 5 to 20% (w/w), wherein the total amount of bothdiluents comprises about 60 to 80% (w/w) of the total weight of thetablet.
 9. A tablet consisting essentially of: a) about 30.4 mgtamoxifen citrate; b) about 1.0 mg anastrozole; c) about 118.0 mglactose monohydrate; d) about 18.0 mg microcrystalline cellulose; e)about 7.2 croscarmellose sodium; f) about 3.6 mg povidone; and g) about1.8 magnesium stearate.
 10. A method for making a pharmaceuticalformulation of tamoxifen citrate comprising: a) dry mixing tamoxifencitrate, anastrozole, lactose monohydrate, microcrystalline cellulose,croscarmellose sodium and povidone to form a dry mixture; b) mixing thedry mixture with water to form a wet granulation; c) breaking up largeaggregates; d) drying the granules to a moisture content of less than orequal to 2% w/w to form dry granules; e) milling the dry granules toform milled dry granules; f) adding a lubricant to the milled drygranules; and g) blending the dry granules containing the lubricant. 11.A method of making a pharmaceutical formulation comprising: a) chargingingredients to a mixer wherein said ingredients comprise tamoxifencitrate, anastrozole, at least one diluent, a disintegrant, and a binderto a mixer; b) mixing the ingredients to form a mixture of ingredientshaving uniform distribution; c) adding water to the mixture ofingredients to form a wet mass; d) passing the wet mass through a screento form granules; e) drying the granules to form dried granules having amoisture content of less than or equal to 2% w/w; f) adding a lubricantto the dried granules to form a lubricant:dried granule mixture; g)milling the lubricant:dried granule mixture; and h) blending the milledmixture to form blended granules.
 12. The method as defined in claim 10or 11 further comprising compressing the granules into a tablet.
 13. Themethod as defined in claim 12, further comprising applying a film coatto said tablet.